Investigator Grant Awards

In 2014, the Texas Council on Alzheimer’s Disease and Related Disorders launched the inaugural Texas Alzheimer’s Research and Care Consortium – Investigator Grant Program, as part of the state-funded Darrell K Royal Texas Alzheimer’s Initiative. This grant program provided financial support to Texas researchers to promote novel research and discovery towards understanding biological mechanisms and developing therapies for Alzheimer’s disease.

Paul C. Trippier, PhD

Title: Identification of Aß-ABAD Interaction Inhibitors for Evaluation as Small Molecule
Therapeutics for the Treatment of Alzheimer’s Disease.

Abstract: Alzheimer’s disease (AD) is the most common form of dementia and memory loss. The disease gets worse over time and is usually associated with advancing age. There is no cure for AD and current drugs only have a minor effect in providing relief of symptoms. One of the major causes of the disease is thought to be the accumulation and aggregation of a protein fragment called beta-amyloid that forms plaques within the brain causing neuron cell death.An enzyme called amyloid binding alcohol dehydrogenase or ABAD has been identified as playing a key role in the development and progression of AD. The enzyme reacts with beta-amyloid causing a chemical reaction that enhances the protein fragments toxic effect and progression of the disease. If the ABAD enzyme is inhibited a protective effect is seen in neurons, which would reduce the severity of the disease. The goal of this project is to identify new compounds that act as inhibitors of the ABAD enzyme. Such compounds will be starting points for the design of potential drugs for the treatment of AD.

Abstract: Memory loss is a common problem in normal aging and is earliest and most recognized symptom in age-associated neurodegenerative diseases including Alzheimer’s (AD) and Parkinson’s disease. Accumulating evidence from clinical and basic studies supports the notion that the effects of estrogen on learning and memory are beneficial. Estrogens have been shown to be useful for the improvement of learning and memory, treatment and prevention or delay of the onset of AD. In addition to these neuroprotective effects of estrogens, estrogens produce female phenotype in both females and males. Moreover, estrogens also increase the risk of female hormone-sensitive cancers such as breast and endometrial cancer. These detrimental effects of estrogen are likely mediated via activation of classical estrogen receptors (ERs) and limit their potential therapeutic for widespread clinical application. Synthetic estrogen analogues, which lack genomic hormonal properties (so-called “nonfeminizing”) may be promising alternatives to natural estrogens to prevent AD- related cognitive decline not only in women but also in men. The ability of estrogen to positively influence cognitive function is likely due at least in part to the fact that it enhances hippocampal long-term potentiation (LTP), the cellular mechanism of long-term memory storage in the brain. Moreover, estrogen modulation of LTP appears to involve a nongenomic mechanism. We have discovered and synthesized over 70 novel nonfeminizing estrogenic compounds. In neuroprotection cell assays, many of these compounds are 10 to 100-time more potent as neuroprotectants than estrogen itself. While the neuroprotection of the nonfeminizing estrogens have been described in vitro and in vivo studies, the cognitive outcomes of such neuroprotection have not been studied. The overall goal of the project is to test the hypothesis that nonfeminizing estrogen analogues have potential utility in improving cognitive function in normal male and female and AD animals. The Specific Aims of the proposal are to: 1) determine whether modulation of hippocampal LTP by nonfeminizing estrogen is dependent on gender, 2) determine whether nonfeminizing estrogen modulates LTP in the brain of AD animal model, 3) determine whether nonfeminizing estrogen attenuates cognitive disorders in a transgenic AD animal model. The proposed experiments will be conducted utilizing in vitro electrophysiological techniques and in vivo behavioral assay. The results of the studies will provide critical evidence needed to demonstrate that nonfeminizing estrogen analogues may provide the cognitive benefits of estrogen without the detrimental side effects, which is the important step towards development of new therapeutics to treat AD. The pilot grant will provide needed resources for accumulating preliminary data essential for submission larger grants to NIH/NIA, state and private foundations.

Anson Pierce, PhD

Assistant Professor
Department of Biochemistry and Molecular Biology
The University of Texas Medical Branch at Galveston
Cynthia Woods Mitchell Center for Neurodegenerative Diseases
Sealy Center for Vaccine Development

Abstract: Impaired proteostasis allowing exposed hydrophobic surfaces on misfolded tau or Trans-activation response DNA binding protein (TDP-43) has been implicated in their aggregation and toxicity in age-associated dementias such as Alzheimer’s disease (AD) and frontotemporal dementia (FTLD). TDP-43 forms inclusions in 57% of AD, 51% of FTLD, and all sporadic amyotrophic lateral sclerosis (ALS), with frequent C-terminal cleavage. We have developed a quantitative covalent proteomic assay to measure surface hydrophobicity of soluble proteins in situ. Using this assay we demonstrate enhanced surface hydrophobicity of TDP-43 and its C-terminal fragments (CTFs). We have observed co-localization of several heat shock proteins (HSPs) to TDP-43 pathology in human AD brain samples. Heat shock factor 1 (HSF1) is a master transcription factor for HSPs. We observed that HSF1 activators protect cells from the pathology and toxicity associated with TDP-43 CTF over-expression. An HSF1 transgenic mouse we developed protects against ALS, and AD-like memory deficits in J20 mice. We will evaluate the biophysical relationship between HSP70 and TDP-43 in vitro and in vivo and determine its ability to mitigate the harmful physical properties of exposed surface hydrophobicity of TDP-43 and its cleavage products. We will test the neuroprotective effects of HSF1 on TDP-43 neuropathology by over-expressing HSF1 in a human TDP-43 overexpressing model. This study will enhance our understanding of the physical properties of soluble TDP-43 aggregates and given the availability of drugs targeting HSF1 activity, identify potential therapeutic avenues that protect against TDP-43 pathology as observed in AD and FTLD.

Abstract: This study addresses two rapidly emerging topics in Alzheimer’s disease (AD); (i) disease-modifying therapy by youthful systemic milieu, and (ii) identification of humoral factors in the youthful milieu that ameliorate AD pathology. Central events in AD include protein misfolding, self-aggregation and cerebral deposition of amyloid-beta (Aβ) as well as neurofibrillary tangles composed of hyperphosphorylated tau. Thus, prevention and removal of amyloidogenic components are considered the most promising strategy to treat AD. We have recently found that youthful systemic milieu provided by whole blood exchange treatment mitigated cerebral deposition of amyloid plaques which reflected in improved spatial memory function in AD model mice. Based on our findings, AD brain reflects the changes in periphery. Thus, elucidating the effects of systemically circulating factors including amyloidogenic components and cytokines on the course of AD may be of great importance to understand the peripheral nature in AD affecting brain pathology of AD. We hypothesize that youthful systemic milieu ameliorates tau pathology. We will address this hypothesis by determining (i) effects of young blood on cerebral deposition of neurofibrillary tangles, tau levels, and behavioral memory (Aim 1), and (ii) identification of humoral factors by comparing cytokines in the plasma and brain interstitial fluid (ISF) in P301S mice receiving youthful systemic milieu (Aim2). To extrapolate the findings in mice to humans, we will essentially utilize Harris Cohort resources. We will compare mouse data with the cytokine profiling in the cerebrospinal fluid and plasma from humans with deferent severity in AD and mild cognitive impairment. Therapeutic combination of humoral factors will have immediate translational advantages.

Abstract: Chemical reactions in eukaryotes are programmed both in time and space; however, external stimuli (environment and disease) continually highjack these processes. The goal of this research is to develop next generation molecular imaging tools that rapidly quantify hard to predict combinatorial chemistry on translated genes in the secretory pathway in the context of normal eukaryote physiology as well as pathobiology associated with Alzheimer’s disease spectrum disorders. Reading qualitative/ quantitative chemical alterations on intact proteins traversing the secretory pathway represents a significant challenge because concentrated-organelle processing leads to extreme chemical heterogeneity (e.g., N-linked glycosylation). To meet this challenge, we propose a novel model: glycoproteoform differential network analysis (GDNA) which will exploit the universality of physiochemical space (hydrophobicity, pI, and mass) covered by a multidimensional proteomics workflow developed in our lab that includes off-gel isoelectric focusing, liquid chromatography, and Fourier Transform Mass Spectrometry (FTMS). We will apply these techniques in longitudinal studies are expected to provide insights on whether abnormal glycosylation patterns observed in CSF of AD patients occur in response to brain insulin resistance or the occurrence of plaque development in and around brain cells.

Huda Zoghbi, MD

Title: A cross-species genetic screen to identify targets that regulate the steady state levels of tau.

Abstract: Alzheimer disease (AD) is characterized by the deposition of amyloid plaques and the accumulation of neurofibrillary tangles, products of APP processing and tau hyperphosphorylation respectively. Several studies demonstrate that reduction of tau is therapeutically beneficial in AD mouse models. This evidence prompted us to hypothesize that modest reduction in the endogenous levels of tau proteins would delay the onset and retard progression of disease. Using a multi-pronged approach we seek to harness innate mechanisms within the cell for regulating tau to find new therapeutic targets and to gain insight in AD pathogenesis. We will identify these pathways using an unbiased, high-throughput RNA interference screen of 7,787 druggable genes. We will employ two different assay systems in parallel (human neuronal cell lines and Drosophila expressing human tau) to identify those proteins whose reduction results in lower levels of tau, and rescue neuronal degeneration phenotypes in Drosophila. Candidates identified in cells and Drosophila will be mapped into an in silco network of modifier genes using computational analyses to pinpoint common pathways converging on the modulation of tau levels. Preliminary studies have revealed new modulators of tau that we are verifying in AD mouse models. We are also testing tool compounds that target or most promising hits. The major goal of this project is to discover new therapeutic targets for Alzheimer’s disease. We propose a research program centered on genes and genetic networks that control tau levels using innovative orthoganol screens of the “druggable” genome. Assembly of the results into canonical regulatory pathways, together with validation using known small molecules, should greatly improve our understanding of the molecular underpinnings of this disorder and accelerate the discovery of new therapeutic leads for the treatment of Alzheimer’s disease.

Abstract: Short-duration exposures to low oxygen (10% O2) interspersed with room air (21% O2) breathing, or intermittent hypoxia (IH), stimulate cyclic responses of heart and lung function, and induces productions of neuroprotective growth/trophic factors that help improve brain health. The objective in this proposed research is to implement a 10-week IH program to improve cognitive function in patients with mild cognitive impairment (MCI) and mild Alzheimer’s disease (MAD). The specific aim is to demonstrate that improvement of cognitive function in MCI/MAD patients after IH conditioning is correlated with serum levels of neuroprotective growth/trophic factors (brain-derived neurotrophic factor, erythropoietin, and vascular endothelial growth factor), and is explained by optimized blood flow and oxygen supply to the brain at rest and during mental stress and physiological challenge. MCI/MAD patients recruited for the proposed research will be selected from a large group of participants who have been enrolled in the studies sponsored by the Texas Alzheimer’s Research and Care Consortium. Proposed follow-up observations after the IH treatment will allow assessing how improved brain health and heart function can slow, stop, or reverse cognitive impairment in these patients during aging process.

The Texas Alzheimer’s Research and Care Consortium is a collaborative Alzheimer’s research effort directed and funded by the Texas Council on Alzheimer’s Disease and Related Disorders, as part of the Darrell K Royal Texas Alzheimer’s Initiative.
Copyright 2016 Texas Alzheimer's Research and Care Consortium | All Rights Reserved | Developed by FlatwareMedia Designs